An artificial blood vessel is a medical device used as an alternative to a living blood vessel suffering from a disease such as arteriosclerosis, or for formation of a bypass or a shunt. Conventional artificial blood vessels can be roughly divided into 1) artificial blood vessels made of a fabric; 2) artificial blood vessels made of polytetrafluoroethylene; 3) artificial blood vessels made of a biomaterial; and 4) artificial blood vessels made of a synthetic macromolecular material. Among these artificial blood vessels, fabric artificial blood vessels made of a woven fabric, knit, or non-woven fabric of fibers have high flexibility, but have a drawback in that blood leakage from gaps between fibers is likely to occur due to blood pressure under actual use conditions. Among fabric artificial blood vessels, knitted artificial blood vessels can be produced by a simple production process, and have flexibility. However, they have lower capacities to maintain their shapes and are likely to have porous structures so that blood leakage is likely to occur through gaps between fibers. Artificial blood vessels made of a non-woven fabric have uneven structures, and have lower capacities to maintain their shapes, which is not preferred.
On the other hand, in fabric artificial blood vessels composed of a woven fabric, the gaps between the fibers can be reduced, and the amount of blood leakage can therefore be reduced unlike artificial blood vessels made of a knit. Therefore, fabric artificial blood vessels composed of a woven fabric are highly demanded in surgery of blood vessels such as aortas. As a method of reducing the amount of blood leakage, a method by reducing the size of each gap between fibers is commonly used. However, in that method, the resulting artificial blood vessel is hard because of an increase in the fiber density. Use of such a hard artificial blood vessel often makes the surgery difficult since both ends of the diseased living blood vessel to be replaced, that is, the living blood vessels to be anastomosed with the artificial blood vessel, are also affected by arteriosclerosis or the like.
In view of this, when a fabric artificial blood vessel is used in blood vessel surgery, a method in which blood leakage is prevented not only by reducing the size of each gap between fibers, but also by giving a bioabsorbable gel such as collagen or gelatin to the gaps between the fibers to fill the gaps, has been reported (JP 3799626 B).
Methods in which the so-called preclotting is carried out have also been reported (JP 5-48132 B and JP 5-88611 B). In the operation of preclotting, a fabric artificial blood vessel is brought into contact with autologous blood immediately before transplantation, to allow formation of thrombi, and the gaps between the fibers are filled with the resulting thrombi to prevent blood leakage.
When an artificial blood vessel is transplanted, the living body recognizes it as a foreign substance, and blood coagulation reaction proceeds on the surface of the artificial blood vessel contacting blood, that is, on the inner surface, leading to formation of thrombi. Therefore, artificial blood vessels require antithrombogenicity.
Conventionally, as a method of increasing the antithrombogenicity of a medical material, a method in which heparin or a heparin derivative is given to a surface of the material has been employed. However, heparin and heparin derivatives cannot be directly given to fabric medical materials made of polyester fibers and the like, and medical materials made of stretched porous polytetrafluoroethylene (hereinafter referred to as “ePTFE”), which constitute artificial blood vessels. In view of this, methods in which a surface of a medical material is modified, and heparin or a heparin derivative is given to the surface of the material by covalent bonding (Japanese Translated PCT Patent Application Laid-open No. 2009-545333, JP 4152075 B and JP 3497612 B), or heparin or a heparin derivative is given to the surface of the material by ionic bonding (JP 60-41947 B, JP 60-47287 B, JP 4273965 B and JP 10-151192 A), have been reported.
As methods of giving antithrombogenicity to a fabric artificial blood vessel, methods in which a bioabsorbable gel used for preventing blood leakage, for example, collagen or gelatin, is impregnated with heparin or a heparin derivative, and the resulting gel is given to a surface of a material (JP 3799626 B and JP 8-24686 B), and a method in which a segmented polyurethane dissolved in an organic solvent is impregnated with heparin or a heparin derivative, and the resulting product is given to a surface of a material (JP 7-265338 A), have been reported.
As methods of increasing the antithrombogenicity of a medical material using a compound having antithrombogenicity other than heparin or heparin derivatives, methods in which a compound(s) that inhibit(s) a plurality of blood coagulation factors involved in the blood coagulation reaction (for example, platelets, which are involved in the stage of primary hemostasis), thrombin, which is involved in the stage of thrombus formation, and/or the like is/are given to a surface of the medical material (JP 4461217 B, WO 08/032758 and WO 12/176861) have been reported.
Living blood vessels have an intima on their inner surfaces, and can inhibit thrombus formation by having vascular endothelial cells. On the other hand, in conventional artificial blood vessels, the cellular affinity is low, and settlement of vascular endothelial cells is less likely to occur. Moreover, settlement of vascular endothelial cells and formation of the intima take a long time. Therefore, not only antithrombogenicity immediately after the transplantation, but also a function to generate cellular affinity with time, have been required.
Examples of reported methods of giving cellular affinity to a fabric artificial blood vessel include methods in which an artificial blood vessel is made such that it has a fiber structure which promotes growth and infiltration of cells such as a method in which the fiber diameter is optimized, and a method in which fluffy, fuzzy, and/or looped fibers are given (JP 61-4546 B, JP 61-58190 B, JP 63-52898 B and JP 5-28143 B).
However, when the method disclosed in JP 3799626 B is used for a fabric artificial blood vessel, the fiber diameter and microstructures such as gaps between fibers for promotion of the cell growth disappear due to the gel such as collagen or gelatin containing heparin or a heparin derivative given to the fiber surface, leading to a decrease in the cellular affinity. Moreover, adhesion of platelets to the bioabsorbable gel such as gelatin rather promotes thrombus formation, which is problematic.
On the other hand, JP 5-48132 B and JP 5-88611 B disclose methods of preparing an artificial blood vessel having a high-porosity structure, that is, a high-water permeability woven structure, to allow quick settlement of vascular endothelial cells on the inner surface of the artificial blood vessel, thereby promoting formation of the intima, or to reduce foreign substances, thereby increasing the biocompatibility, respectively. However, preclotting is indispensable in these methods, and the fiber diameter and microstructures such as gaps between fibers disappear due to thrombi formed by this operation, leading to a decrease in the cellular affinity. In blood vessel surgery, an anticoagulant (for example, heparin or argatroban) is commonly used for prevention of blood coagulation during the surgery, and the blood vessel is therefore in a state where a thrombus is less likely to be formed. Thus, in some cases, the gaps between the fibers cannot be sufficiently filled by the preclotting. Furthermore, in some cases, thrombi formed by the preclotting are melted due to the action of the fibrinolytic system in blood after the surgery, leading to blood leakage.
Japanese Translated PCT Patent Application Laid-open No. 2009-545333, JP 4152075 B, JP 3497612 B, JP 60-41947 B, JP 60-47287 B, JP 4273965 B and JP 10-151192 A describe methods in which heparin or a heparin derivative is given to a surface of a medical material by covalent or ionic bonding of the heparin or the heparin derivative to a surface modifier. However, in terms of use of a fabric artificial blood vessel having a fiber diameter and/or a microstructure such as gaps between fibers for promotion of the cell growth, those publications do not describe an appropriate thickness of the antithrombogenic material layer composed of the surface modifier and the heparin or the heparin derivative.
JP 8-24686 B and JP 7-265338 A describe methods in which a bioabsorbable gel containing heparin or a heparin derivative, or an antithrombogenic material dissolved in an organic solvent, is physically given to a surface of a medical material. Since, in those methods, the antithrombogenic material layer is thick, the fiber diameter and microstructures such as gaps between fibers for promotion of the cell growth disappear.
Similarly, JP 4461217 B, WO 08/032758 and WO 12/176861 describe methods in which two compounds having both anti-platelet adhesion capacity and antithrombin activation capacity, or a compound prepared by giving both anti-platelet adhesion capacity and antithrombin activation capacity to a single molecule, is/are immobilized on a surface of a medical material. However, in terms of use for a fabric artificial blood vessel having a fiber diameter and/or a microstructure such as gaps between fibers for promotion of the cell growth, those publications do not describe appropriate thickness of the antithrombogenic material layer composed of such a compound(s).
JP 61-4546 B, JP 61-58190 B, JP 63-52898 B and JP 5-28143 B disclose artificial blood vessels having cellular affinity prepared using a fiber of not more than 0.5 denier, that is, not more than 0.56 dtex, for at least a part of the inner surface. However, since antithrombogenicity, which is required immediately after the transplantation, is not given to those artificial blood vessels, they cannot suppress thrombus formation. Although a method of increasing the cellular affinity by giving fluffy, fuzzy, and/or looped fibers has been disclosed, such a method has a problem in that an additional step of forming the fluffy, fuzzy, and/or looped fibers is required, and that this additional step produces waste fibers whose elution into blood may occur. Moreover, that method has a problem in that, since disturbance of the fiber directions of the warp yarns and the weft yarns increases, settlement of vascular endothelial cells is less likely to occur, and the cellular affinity therefore decreases.
That is, at present, there is no artificial blood vessel composed of a cylindrical fabric structure that allows only a small amount of blood leakage and can achieve both the antithrombogenicity and the cellular affinity. In particular, in a small-diameter artificial blood vessel having an inner diameter of less than 6 mm, thrombi are likely to be formed because of low blood flow, and even a small thrombus may have a size comparable to the inner diameter of the blood vessel. Thus, inhibition of the blood flow is likely to occur. Therefore, small-diameter artificial blood vessels show poor long-term performances, and none of them is clinically useful at present.
It could therefore be helpful to provide a fabric artificial blood vessel that allows only a small amount of blood leakage and can achieve both the antithrombogenicity and the cellular affinity.